Role of Calpains in Axonal Injury and Degeneration

Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury (TBI), spinal cord injury, cerebral ischemia, neurodegenerative diseases, and demyelinating and hereditary neuropathies. The calpain family of proteases has been causally linked to many of these acute and chronic disorders. In particular, previous studies have suggested that pathologic calpain activity may be responsible for axonal dysfunction and degeneration. Even though the immediate cause of increased intra-axonal calpain activity varies, the downstream effects of calpains may be similar. To address the role of calpains in axonal injury, I have relied on two animal models: nerve transection and optic nerve stretch. First, I demonstrated that overexpression of the endogenous calpain inhibitor, calpastatin, in transgenic mice provided biochemical and morphological protection to transected PNS axons, and biochemical protection to CNS axons. I then studied the role of calpains in synaptic dysfunction in transected PNS axons. There was no detectable protection of synaptic function with calpastatin overexpression. Next, I developed and characterized a new in vivo model of optic nerve stretch that isolates mechanical strain primarily to axons of retinal ganglion cells in the rat. This model of optic nerve stretch recapitulates the signature pathology seen in axons after human TBI, which is transport disruption. Within my study of optic nerve stretch, I used both the pharmacologic calpain inhibitor MDL-28170 and adeno-associated viral vector-mediated overexpression of calpastatin to examine the role of calpains in impairment of retrograde transport after mechanical stretch of axons. Calpastatin overexpression, but not short-duration MDL-28170, protected retrograde axonal transport. Taken together, my dissertation work extends our understanding of the pathologic role of calpains in axonal injury and degeneration

On Reconciling Gottfried Sum Rule Violation with Cabibbo Theory

We discuss the seemingly contradictory constraints of simultaneously preserving the SU(3)-symmetric Cabibbo description of the weak vector baryon matrix elements, accounting for SU(3) flavor symmetry breaking and describing the observed violation of the Gottfried Sum Rule. We try to construct a simple model that will satisfy these constraints and use it to explain the generic difficulties and tradeoffs.Comment: 10 pages, late

3D modelling of long-term sulfide corrosion of copper canisters in a spent nuclear fuel repository

Copper canisters are a central component in the safety of the Finnish spent fuel repository concept (KBS-3), where the main corrodent potentially affecting the canister integrity is sulfide. In this study, a 3D numerical model is developed to assess the evolution of sulfide fluxes and the spatially resolved canister corrosion depths for the Finnish spent nuclear fuel repository concept. The backfilled tunnel and the disposal hole are implemented using repository geometries, with sulfide being produced at their interface with the rock (excavation damaged zone) by sulfate reducing bacteria (SRB). Recent experimental findings regarding the microbial sulfate reduction process as well as the scavenging of sulfide via iron (oxy)hydroxides are incorporated in the reactive transport model. Long-term simulations are performed, predicting a heterogeneous corrosion of the canister with a max. corrosion depth of 1.3 mm at the bottom corner after one million years. The evolution of sulfide fluxes shows two main phases, depending on the source of sulfate: first sulfate is supplied by the dissolution of gypsum from the bentonite barriers, followed by a steady, low-level supply from the groundwater. Sensitivity cases demonstrate that both the organic carbon and Fe(III) oxide contents in the bentonite are critical to the corrosion evolution, by being the main electron donor for SRB activities and the major sulfide scavenger in the bentonite, respectively. The backfilled tunnel contributes little to the flux of corrosive sulfide to the canister due to the attenuation by Fe(III)-oxides/hydroxides but induces a notable flux of sulfate into the disposal hole

SNS optical fiber sensor for direct detection of phase transitions in C18H38 n-alkane material

A single-mode-no-core-single-mode (SNS) fiber optical sensor for the detection of solid-liquid and liquid-solid phase changes in C18H38 n-alkane (n-octadecane) is proposed and demonstrated. The transmission-type sensor probe consists of a short section of no-core fiber sandwiched between two sections of a single-mode fiber. Phase changes in n-octadecane are accompanied by large step-like variations of its refractive index (RI). Such a large discontinuous change of the n-octadecane’s RI during its phase transition leads to the corresponding step-like change in the transmitted optical power that can reliably indicate the phase change of the sample in the vicinity of the sensor. The proposed sensor probe is simple, accurate and is capable of detecting the material’s phase based on a single measurement. The results of this work suggest that the proposed sensor is potentially capable of detecting liquid-solid phase changes in other materials whose thermo-optic properties are similar to those of n-octadecane

Ultrasonography and color Doppler of proximal gluteal enthesitis in juvenile idiopathic arthritis: a descriptive study

Background: The presence of enthesitis (insertional inflammation) in patients with juvenile idiopathic arthritis (JIA) is difficult to establish clinically and may influence classification and treatment of the disease. We used ultrasonography (US) and color Doppler (CD) imaging to detect enthesitis at the small and deep-seated proximal insertion of the gluteus medius fascia on the posterior iliac crest where clinical diagnosis is difficult. The findings in JIA patients were compared with those obtained in healthy controls and with the patients' MRI results. Methods: Seventy-six proximal gluteus medius insertions were studied clinically (tenderness to palpation of the posterior iliac crest) and by US and CD (echogenicity, thickness, hyperemia) in 38 patients with JIA and in 38 healthy controls, respectively (median age 13 years, range 7-18 years). In addition, an additional MRI examination of the sacroiliac joints and iliac crests was performed in all patients. Results: In patients with focal, palpable tenderness, US detected decreased echogenicity of the entheses in 53% of the iliac crests (bilateral in 37% and unilateral in 32%). US also revealed significantly thicker entheses in JIA patients compared to healthy controls (p < 0.003 left side, p < 0.001 right side). There was no significant difference in thickness between the left and right sides in individual subjects. Hyperemia was detected by CD in 37% (28/76) of the iliac crests and by contrast-enhanced MRI in 12% (6/50). Conclusions: According to US, the gluteus medius insertion was thicker in JIA patients than in controls, and it was hypoechoic (enthesitis) in about half of the patients. These findings may represent chronic, inactive disease in some of the patients, because there was only limited Doppler flow and MRI contrast enhancement. The present study indicates that US can be useful as an adjunct to clinical examination for improved assessment of enthesitis in JIA. This may influence disease classification, ambition to treat, and choice of treatment regimen

Uniaxial transition dipole moments in semiconductor quantum rings caused by broken rotational symmetry

Semiconductor quantum rings are topological structures that support fascinating phenomena such as the Aharonov-Bohm effect and persistent current, which are of high relevance in the research of quantum information devices. The annular shape of quantum rings distinguishes them from other low-dimensional materials, and enables topologically induced properties such as geometry-dependent spin manipulation and emission. While optical transition dipole moments (TDMs) in zero to two-dimensional optical emitters have been well investigated, those in quantum rings remain obscure despite their utmost relevance to the quantum photonic applications of quantum rings. Here, we study the dimensionality and orientation of TDMs in CdSe quantum rings. In contrast to those in other two-dimensional optical emitters, we find that TDMs in CdSe quantum rings show a peculiar in-plane linear distribution. Our theoretical modeling reveals that this uniaxial TDM originates from broken rotational symmetry in the quantum ring geometries

Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit

Alterations in the expression, molecular composition, and localization of voltage-gated sodium channels play major roles in a broad range of neurological disorders. Recent evidence identifies sodium channel proteolysis as a key early event after ischemia and traumatic brain injury, further expanding the role of the sodium channel in neurological diseases. In this study, we investigate the protease responsible for proteolytic cleavage of voltage-gated sodium channels (NaChs). NaCh proteolysis occurs after protease activation in rat brain homogenates, pharmacological disruption of ionic homeostasis in cortical cultures, and mechanical injury using an in vitro model of traumatic brain injury. Proteolysis requires Ca2+ and calpain activation but is not influenced by caspase-3 or cathepsin inhibition. Proteolysis results in loss of the full-length {alpha}-subunits, and the creation of fragments comprising all domains of the channel that retain interaction even after proteolysis. Cell surface biotinylation after mechanical injury indicates that proteolyzed NaChs remain in the membrane before noticeable evidence of neuronal death, providing a mechanism for altered action potential initiation, propagation, and downstream signaling events after Ca2+ elevation